title: Brevenal inhibits pacific ciguatoxin-1B-induced neurosecretion from bovine chromaffin cells.
abstract: Ciguatoxins and brevetoxins are neurotoxic cyclic polyether compounds produced by dinoflagellates, which are responsible for ciguatera and neurotoxic shellfish poisoning (NSP) respectively. Recently, brevenal, a natural compound was found to specifically inhibit brevetoxin action and to have a beneficial effect in NSP. Considering that brevetoxin and ciguatoxin specifically activate voltage-sensitive Na+ channels through the same binding site, brevenal has therefore a good potential for the treatment of ciguatera. Pacific ciguatoxin-1B (P-CTX-1B) activates voltage-sensitive Na+ channels and promotes an increase in neurotransmitter release believed to underpin the symptoms associated with ciguatera. However, the mechanism through which slow Na+ influx promotes neurosecretion is not fully understood. In the present study, we used chromaffin cells as a model to reconstitute the sequence of events culminating in ciguatoxin-evoked neurosecretion. We show that P-CTX-1B induces a tetrodotoxin-sensitive rise in intracellular Na+, closely followed by an increase in cytosolic Ca2+ responsible for promoting SNARE-dependent catecholamine secretion. Our results reveal that brevenal and beta-naphtoyl-brevetoxin prevent P-CTX-1B secretagogue activity without affecting nicotine or barium-induced catecholamine secretion. Brevenal is therefore a potent inhibitor of ciguatoxin-induced neurotoxic effect and a potential treatment for ciguatera.
authors.affiliation: CNRS, Institut de Neurobiologie Alfred Fessard, Laboratoire de Neurobiologie Cellulaire et Moléculaire, Gif-sur-Yvette, France.
authors.forename: César
authors.initials: C
authors.lastname: Mattei
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wen
authors.forename: Truong D
authors.initials: TD
authors.lastname: Nguyen-Huu
authors.forename: Martha
authors.initials: M
authors.lastname: Alvarez
authors.forename: Evelyne
authors.initials: E
authors.lastname: Benoit
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Bourdelais
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Baden
authors.forename: Jordi
authors.initials: J
authors.lastname: Molgó
authors.forename: Frédéric A
authors.initials: FA
authors.lastname: Meunier
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D019439:Chromaffin Cells / Q000187:drug effects / Q000378:metabolism*; D036841:Ciguatera Poisoning / Q000188:drug therapy*; D002922:Ciguatoxins / Q000494:pharmacology*; D009489:Neurosecretion / Q000187:drug effects*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels; D013874:Thiopental / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000931:Antidotes; D002395:Catecholamines; D015222:Sodium Channels; D002922:Ciguatoxins; C004316:thiobutabarbital; D012964:Sodium; D013874:Thiopental; D002118:Calcium